Analgesic Effects of Ketamine, Magnesium Sulfate, and Sodium-Thiopental on Propofol Injection Pain: A Single-Blind Randomized Clinical Trial.

Background
Propofol is one of the most frequently used medications for inducing and maintaining anesthesia. However, propofol injection causes pain and discomfort in more than 70% of patients. This study was performed to determine the comparative effects of ketamine, sodium-thiopental, and magnesium sulfate on reducing pain at the onset of anesthesia induced by propofol injection.


Materials and Methods
This single-blind randomized clinical trial was conducted on a population of patients, requiring nonemergency surgeries. The sample size was determined as 25 patients per group. The eligible samples were randomly divided into three groups. An 18-gauge intravenous catheter was inserted in the dorsum of the hand for all patients. Three groups received 0.5 ml/kg of ketamine, 30 mg/kg of magnesium sulfate, and 0.5 ml/kg of sodium-thiopental, respectively. Next, 2.5 mg/kg of propofol 2% was administered at a rate of 1 ml/s. The verbal rating scale (VRS) was applied to assess the severity of pain during injection.


Results
According to the results, the prevalence of pain was 36% in the magnesium sulfate group, 16% in the sodium-thiopental group, and 4% in the ketamine group. The ordinal logistic regression test showed that patients from the ketamine group experienced less pain, compared to the magnesium sulfate group (OR, 0.045; P= 0.008). However, no significant difference was observed between the ketamine and sodium-thiopental groups (OR, 0.253; P= 0.283).


Conclusion
Ketamine and sodium-thiopental can be effective medications in reducing pain caused by propofol injection. According to the results, magnesium sulfate is not recommended for reducing pain due to propofol injection.


INTRODUCTION
Propofol is one of the most common medications for inducing and maintaining anesthesia, with advantages such as rapid action and recovery. However, propofol injection causes pain and discomfort in more than 70% of patients (1). There are different strategies to prevent pain on propofol injection, including adjustment of injection speed, carrier fluid (2), solvent (3), and concomitant use of drugs.
However, the side effects of these medications should be taken into consideration.
Ketamine is another drug with analgesic effects, used in anesthesia induction. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with strong analgesic effects, even at low concentrations. Some studies have revealed that ketamine can significantly reduce the pain caused by propofol injection (8,9). Magnesium sulfate is another drug used to reduce propofol-induced pain. It is a natural calcium antagonist, which can be used as an adjuvant agent to reduce postoperative pain (10)(11)(12). Various studies have shown that magnesium sulfate can reduce the need for opiates, such as propofol, remifentanil, and vacuronium (10,13,14). Another study compared the effects of magnesium sulfate and normal saline on propofol injection pain and showed greater pain reduction in the magnesium sulfate group, compared to the normal saline group (15).
Sodium-thiopental is another frequently used anesthetic agent. In this regard, the results of a study on children showed that a mixture of sodium-thiopental and propofol can lead to a greater reduction of pain, caused by propofol injection (16). Another study showed that concomitant use of sodium-thiopental and propofol can significantly reduce propofol injection pain, even with 10% sodium-thiopental (17).
The pain caused by propofol injection is still a common problem in anesthesia. Considering its extensive use and necessity of mitigating the associated complications, examination of various strategies seems essential.
The present study was conducted to determine the comparative effects of ketamine, sodium-thiopental, and magnesium sulfate on reducing propofol injection pain at the onset of anesthesia.

Study design
This single-blind, parallel-design, randomized clinical trial was conducted on a population of patients, requiring nonemergency surgeries at Booali Hospital of Sari, Iran.
The inclusion criteria were age range of 18-65 years and class I and II ASA, while the exclusion criteria were highly increased intracranial pressure, unstable hemodynamics, severe mental disorders, history of allergy to drugs, kidney, liver, or heart dysfunction, addiction, and use of calcium or magnesium blockers.

Sample size
Considering 90% confidence interval, 80% power, and 30% difference based on a previous study (18), the sample size was determined as 25 patients for each group. After obtaining approval from the Ethics Committee of Mazandaran University of Medical Sciences and collecting informed consents from the patients, eligible samples were randomly divided into three groups.

Intervention
Before the intervention, an 18-gauge intravenous catheter was inserted in the dorsum of the hand for all patients. One minute prior to propofol injection, all patients received the study drug through a 5 mL syringe.
In the ketamine group, the patients received 0.5 ml/kg of ketamine (production series, 11-207; Trittau, Germany) (18). In the magnesium sulfate group, magnesium sulfate (production series, 1228054891; Pasteur Institute, Iran) was administered at a concentration of 30 mg/kg (10,(12)(13)(14), and in group three, the patients received 0.5 ml/kg of sodium-thiopental (19) (production series, 207; Trittau, Germany) at a rate of 1 mg/sec. Next, 2.5 mg/kg of propofol 2% (production series, 34209; Melsungen, Germany) was administered at a rate of 1 ml/sec. The verbal rating scale (VRS) was immediately used after injection of drugs to assess the severity of pain during injection (20)(21)(22). It involved facial expressions, withdrawal of the hand, tears, and complaints about pain (further explanation required, particularly about score rating).
In the VRS, "none" describes patients who experience no pain; "mild pain" describes patients who respond to

Randomization
After obtaining approval from the Ethics Committee of Mazandaran University of Medical Sciences and collecting written informed consents from the patients, they were assured of the confidentiality of data. The eligible participants were then given a brief description about the study. The participants were randomly divided into three groups via block randomization method. Recruitment of participants was sequential in the study. The samples were also blind to the type of intervention.

Statistical analysis
The severity of pain was evaluated with VRS and compared between the groups, using the ordinal logistic regression model. Numerical data are presented as mean and standard deviation. Data were analyzed in SPSS version 20, and the significance level was set at P< 0.05.

RESULTS
A total of 71 patients were recruited in this study   According to the results, the prevalence of pain was 36% in the magnesium sulfate group, 16% in the sodiumthiopental group, and 4% in the ketamine group.    The results of the present study showed no significant difference in pain between the sodium-thiopental and ketamine groups. Overall, many studies have examined

Conflict of interests
The authors have no conflict of interests to declare